The present invention provides a new use of known pharmaceutical compounds. In particular the present invention provides a method for reducing the side effects associated with anticancer drug irinotecan by the prior coadministration of anticancer drug tamoxifen.
In humans, irinotecan hydrochloride, the active ingredient in CAMPTOSAR Injection, induces a potentially life-threatening intestinal toxicity (diarrhea). We have been studying the mechanism for this toxicity with the goal of identifying an intervention therapy. In previous hamster studies we found irinotecan to block intestinal epithelial cells in the G.sub.2 phase of the cell cycle concurrent with the onset of diarrhea). We believe this G.sub.2 block reduces intestinal epithelial cell differentiation (a G.sub.1 -associated process), resulting in a loss of physiological function and the onset of diarrhea. Based on our findings, we claim that blocking normal epithelial cells in G.sub.0 /G.sub.1 would prevent entry into S phase and thus protect these cell against CPT-11 (SN-38) toxicity. Tamoxifen, a marketed antiestrogen chemotherapeutic agent, is known to induce a block in the G.sub.0 /G.sub.1 phase of the cell cycle.
As seen below, we show that tamoxifen: 1) enhances the recovery of a non-tumor cell line from SN-38-induced inhibition but enhances the toxicity of SN-38 in a tumor cell line; 2) reduces weight loss attributable to diarrhea in hamsters treated with CFT-11, 3) reduces the colonic pathology and physiological effects induced in the hamster by CPT-11. These findings indicate a potential therapeutic benefit in coadministration of tamoxifen as a protective agent prior to and along with CPT-11.